Food materials for prevention of carious degradation of teeth

ABSTRACT

Cariogenic substances such as foodstuffs are treated to incorporate a soluble source of calcium or phosphate ions to provide a product of calcium and phosphate ion concentrations in fluids of salivary retention areas preclusive of carious dissolution of dental enamel. In non-aqueous foodstuffs, the calcium or phosphate ion source should be at least as rapidly soluble as cariogenic, e.g., carbohydrate, components therein. Also provided are mouth rinse solutions comprising a soluble source of calcium or phosphate ions and an osmotically active agent effective in delivering such ions to fluids trapped in salivary retention areas.

BACKGROUND

This is a division of application Ser. No. 139,199, filed Apr. 11, 1980,now U.S. Pat. No. 4,405,600, as a continuation-in-part of applicationSer. No. 46,314, filed June 7, 1979 and now abandoned.

The present invention relates generally to prevention of dental cariesand more specifically provides: methods for lessening the cariogenicityof materials to be placed in the oral cavity; products, especiallyfoodstuffs, treated according to such methods to have substantiallydiminished cariogenic effects when taken into the mouth; and methods andmaterials for treating the oral cavity to counteract or neutralize theeffects of cariogenic materials present in salivary retention areas.

The incidence of dental caries is pandemic, resulting in enormousdiscomfort to dental patients and huge expenditures of monetaryresources. The prior art is rich in proposals for prophylactic andrestorative treatments respecting carious degradation of teeth. Suchtreatments may be grossly classified into two groups, (1) "localized"applications of materials directly to the mouth, and (2) "systemic"(generally dietary) treatments. Both groups of treatments focus onpreserving the integrity of crystalline minerals from which the teethare formed and consequently there often exists a degree of similarity intreating agents employed.

"Localized" treatments generally consist either of routine applicationof dental preparations (toothpastes, mouthwashes, and the like) whichcontain relatively dilute concentrations of various soluble andinsoluble agents, or periodic administration of similar substances inmore concentrated form. A first type of routine treatment has as itsgoal the reduction of population of flora and consists of application ofbactericidal or bacteriostatic agents. Such treatments are not pertinentto the present invention.

Toothpastes routinely employed in the art may consist simply of abrasivematerials whose function is to wear away dental plaque (see, e.g., U.S.Pat. No. 3,629,398), but more often toothpastes contain a wide varietyof elements in combinations substantially duplicating the mineralcontent of the teeth. U.S. Pat. No. 4,048,300, for example, disclosesdental creams containing, inter alia, abrasive minerals. The assertedfunction of such dental creams is to provide not only a source ofplaque-removing abrasives, but also to topically "remineralize" exposedtooth surfaces which may have been selectively demineralized in earlystages of caries formation. Many toothpastes include fluoride ionsources in low concentrations (see, e.g., U.S. Pat. No. 3,885,028) andrecent reports have indicated that use of mouthwashes comprising a 0.2percent solution of sodium fluoride is effective in reducing theincidence of dental caries in children.

The most common long-term periodic treatments are also aimed at"remineralization" and involve applying concentrated solutions andsuspensions of one or more of the twenty-one elements ordinarily presentin the tooth itself. Especially preferred treatments include fluorinesalts or calcium and phosphate ion sources. U.S. Pat. No. 4,083,955, forexample, discloses allegedly beneficial remineralization processesinvolving sequential application of separate compositions providingcalcium ions or phosphate ions. U.S. Pat. No. 4,080,440 disclosesapplication of a metastable, low pH, mixture of soluble sources ofcalcium and phosphate ions which preferably contains a source offluorine ions. Both these types of applications specifically acknowledgea basic problem inherent in locally supplying calcium and phosphate ionsto the tooth surface, i.e., the rapid formation of relatively insoluble(and ineffective) calcium phosphate or calcium fluoride salts uponadmixing ion sources in solution. As another example, U.S. Pat. No.3,978,206 discloses dental products and appliances made with ionexchange resins containing calcium, phosphate and fluorine ions, whichresins are said to bypass the calcium phosphate and/or calcium fluorideprecipitation problem.

"Systemic" treatments of the prior art are frequently aimed atmaintaining and/or elevating "whole body" levels of calcium,phosphorous, fluorine and other elements in order to directly orindirectly provide an enhanced storehouse of materials for naturalmineralization and, assertedly, remineralization of teeth. Treatment ofwater supplies to provide a dietary intake of fluorine on the order ofone-half to one part per million is generally acknowledged as producingsalutory cariostatic effects on children during the years of permanenttooth formation. Once teeth have been fully formed, however, suchsystemic fluoride treatments are generally held to be ineffective inpreventing caries and, despite immense research efforts, the mechanismof action of fluorine in retarding tooth decay remains unclear.

Substantial efforts in the prior art have also been directed towardsupplementing dietary intake of calcium, phosphorous and other elements,for the purpose of providing long term cariostatic effects. See, e.g.,Limbustu, et al., J.D. Res., 39, No. 4, p.722 (1960); Dalderup, J.D.Res., 38, No. 6, pp. 1173-7 (1959); McClure, et al., J.D. Res., 38, No.4, pp. 776-781 (1959); and McClure, et al., J.A.D.A., 58, pp. 36-41(1959). Wynn, et al., J.D. Res., 39, No. 6, pp. 1148-1151 (1960)provides an excellent analysis of prior experimental studies on thecariostatic effects of various calcium and phosphorous supplementeddiets, concluding the results are frequently contradictory for whollyunexplainable reasons. See also, Limbasuta, "Studies on the Preventionof Experimental Dental Caries in Rats with Calciu, Phosphate andFluoride Compounds", M.S. Thesis, The University of Rochester,Rochester, N.Y., 1961.

The published literature in this area is currently said to contain over100 reports of caries preventative action resulting from increasedintake by experimental animals of phosphates, alone and in combinationwith other metal ions (including calcium) as well as in combination witha source of fluorine. Systemically administered phosphates are said todiffer in cariostatic activity depending on the type of anion(cyclictrimeta-, hexameta-, ortho-, and pyrophosphate, increasing ineffectiveness in that order). Compounds of the same phosphate series arealso said to vary in activity depending on the cation (hydrogen, sodium,potassium, ammonium, calcium and magnesium, decreasing in that order).The more pertinent studies of this type have indicated that cariostaticeffects of phosphates appeared to be due in part to direct action ofphosphate on the teeth as food passes through the mouth, as well as tothe return of phosphate to the mouth as a salivary constituent. See,"Minerals; Calcium and Phosphorus" by R. S. Harris, appearing in"Dietary Chemicals vs. Dental Caries" Advances in Chemistry Series, 94,at pp. 116-122 (Americal Chemical Society, Washington, D.C. 1970).

Also pertinent to the background of the invention are prior artproposals for solubilization of normally insoluble phosphates tofacilitate their transport and utilization in biological systems. U.S.Pat. Nos. 3,375,168 and 3,394,916, for example, are directed to methodsfor forming solubilized complexes of sugars and inorganic phosphates.Such complexes are said to be useful both in remineralization of teeth(when incorporated in toothpastes) and as components of cariostaticdiets. As another example, U.S. Pat. No. 4,022,887 treats thepreparation of edible cyclotriphosphates and cyclotetraphosphates andtheir asserted use as phosphorous supplements in caries-inhibitingdiets.

The above-noted prior art developments have unfortunately resulted inonly minor advances in prevention of carious degradation of teeth. Todate, none of the alleged short term or long term "remineralization"processes has been shown to be consistently effective and, with thepossible exception of water fluoridation, none of the proposed dietarysupplementation schemes has uniformly resulted in significant reductionin the incidence of dental caries. Indeed, in many instances theproposed methods and materials have proven to have deleterious sideeffects. Long term exposure to water having fluorine levels of ten partsper million or more results in mottling of teeth. Indeed, great caremust be taken in administering concentrated sodium and stannous fluirideto teeth in order to avoide poisoning of the patient.

As further background to the present invention it is to be noted thatdental enamel (the hard, glistening substance covering the exposedportions of the teeth) is composed chiefly of hydroxyapatite with smallamounts of carbonate, magnesium, fluoride and an organic matrix (about0.5 percent) of glycoprotein and a keratin-like protein. Structurally,enamel is made up of oriented rods, each of which consists of a stack ofrodlets encased in an organic prism sheath. Carious dental enamel isgenerally recognized to result from the selective dissolution of apatitecrystallites of varying size and shape.

In vitro model studies by the inventor and his co-workers haveestablished that the selective demineralization of intact enamelresembling in vivo dental caries is accomplished not simply by acidtreatment but by, e.g., exposure to aqueous inorganic and organic acidsolutions which are less than fully saturated with calcium and phosphateions.

The dissolution/demineralization process in such systems is generallyseen to continue until the acid medium in contact with the tooth surfacebecomes essentially satuarated with dissolved calcium and phosphateions, whereupon dissolution ceases unless events occur which again bringabout a relative unsaturation of the aqueous medium. If, for example, itoccurs that the acidity of the medium is increased (either by additionof hydrogen ions directly or by formation of hydrogen ions by salivaryflora) the demineralization process will again be initiated. Within thiscontext one can envision the following model of the events leading up tocarious degradation of enamel surfaces.

In the oral cavity, enamel surfaces are continuously bathed withsalivary fluid which normally has a pH within the range of 6.5 to 7.5and is essentially saturated with calcium ions (about 0.058 mg/ml) andphosphate ions (about 0.168 mg/ml). No dissolution of enamel willordinarily occur unless the pH of the saliva in direct contact with thetooth surface is reduced, resulting in relative unsaturation withcalcium and phosphate ions. Decreases in salivary pH may occur rapidly,as when highly acidic material is taken into the mouth, or relativelygradually, as when salivary flora metabolize refined sugar and othercarbohydrates. Owing to the constant flow of salivary fluid into themouth, the aforementioned gradual pH changes seldom occur in salivacontacting fully exposed enamel surfaces. Gradual changes frequentlyoccur, however, in so-called "small spaces" or "salivary retentionareas", i.e., areas of contact between adjacent teeth or between dentalor orthodontic appliances and teeth, small pits or grooves in enamelsurfaces, and at the site of adherence of dental plaque.

As a result of experimental work by the inventor and his co-workers, ithas long been accepted that hydrostatic forces affecting fluids in theseconfined spaces substantially preclude the physical displacement ofretained saliva by ordinary parotid fluid flow. Bacterial fermentationof sugars and the like is thus permitted to proceed in these spacesessentially undisturbed and can result in dramatic pH drops in retainedsaliva within a matter of minutes or hours depending upon the bacterialcount within the narrow space, even though salivary flow in the mouth isaltogether normal. Such drops in pH, as noted above, provide anenvironment conducive to selective dissolution of enamel.

The cariogenicity of fluids retained in salivary retention areas isfurther enhanced by osmotic forces extant in the oral cavity. Oralintake of foods having soluble refined sugars and other cariogenicsubstances will, of course, result in enhancement of food supplies forbacteria in salivary retention areas. Despite the general inability offlowing saliva to displace retained saliva, osmotic differentialsbetween "trapped" saliva and saliva containing dissolved sugars willresult in migration of these bacterial nutrients into salivary retentionareas. To the extent that there is a tendency for dissolved sugars andthe like to migrate from salivary retention areas across hydrostaticforce barriers and into fresh flowing saliva (thereby effecting adepletion of bacterial food supplies), so also is there a tendency forretained fluids to be similarly depleted of their "normal" complementcalcium and phosphate ions because the ions migrate along with theosmotically active substances. This results in an amplification ofunsaturation of retained saliva with respect to these ions, so thatfluids of even moderately low pH will have more extensive cariogeniceffect. In sum, both hydrostatic and osmotic force effects in the mouthtend to create a medium in the salivary retention areas which isparticularly conducive to carious degradation of enamel. Indeed, it isprecisely in these areas that the highest incidence of dental caries isencountered. Similarly, the most highly cariogenic foodstuffs have beenfound to be acidic fluids having high concentrations of refined sugarsin a dissolved state.

Review of prior art developments within the context of the aboveanalysis of events taking place in the oral cavity provides anexplanation for the very limited successes that have been achieved inthe art. Simply put, none of the prior proposals have adequately takeninto consideration and accommodated for the dynamic hydrostatic andosmotic forces at the localized level of salivary retention areas withinthe mouth. Apart from bactericidal compositions which inhibit bacterialpropagation upon transport of active agents into these areas, none ofthe prior art localized treatments have been designed to mitigate theadverse effects of bacterial proliferation in terms of decreased pH andconsequent calcium and phosphate ion "imbalances". Further, no prior artmethods and materials have had as their focus the "neutralization",prior to oral intake, of the ion-imbalancing, cariogenic effects offoodstuffs containing refined sugars and other soluble carbohydrates.

SUMMARY

In one aspect, the present invention provides novel methods andmaterials for treating the mouth to counteract the deleterious effectsof cariogenic substances present in salivary retention areas. Anembodiment of this aspect of the invention is an aqueous mouth rinsecomprising either a soluble source of calcium ions or a source ofphosphate ions together with a non-toxic, osmotically active substanceproviding for transport of the selected ions into salivary retentionareas. The quantity of selected ions in the rinse is such that therewill be supplied to the salivary retention areas sufficient ions toexceed the pH dependent product of calcium and phosphate (as totalphosphorous) ion concentrations at which dissolution of enamel will nottake place.

Another aspect of the invention provides novel methods for treatingcariogenic substances such as refined sugar and acidic foodstuffs to"neutralize" their cariogenic effects. In one embodiment, mixtures ofrefined sugar and a selected, soluble, calcium or phosphate salt areprepared e.g., by solution and recrystallization. The concentration ofcalcium or phosphate ion source in the sugar mixture is such as willsupply salivary retention aras with sufficient ions to exceed theabove-noted ion concentration product. Sugar treated in this manner maythen be substituted for non-treated refined sugar in foodstuffs. It isof substantial importance that the calcium or phosphate ion source be asrapidly soluble in saliva as the sugar so that the protective ions willmigrate to salivary retention areas as rapidly as the sugar.

In another embodiment highly cariogenic foodstuffs such as acidic,sugar-containing soft drinks are treated to augment calcium and/orphosphate ion concentrations so that acid or bacterial nutrientmaterials transported into salivary retention areas will be accompaniedby calcium and/or phosphate ions in amounts sufficient to preventdissolution of enamel despite rapid or gradual increments in acidity ofthe retained fluids.

Other aspects and advantages of the present invention will becomeapparent upon consideration of the following detailed description.

DETAILED DESCRIPTION

As indicated above, the present invention has its origins in prior workby the inventor and his co-workers concerning two distinct andheretofore unrelated phenomena, i.e., (1) the relative stability of theionic constitution of fluids within salivary retention areas of themouth, and (2) the variable cariogenicity of acid solutions comprisingcalcium and phosphage ions in varying relative concentrations, asdemonstrated by in vitro studies.

The more pertinent of the inventor's early publications concerning therelative stability of fluids in salivary retention areas include J.D.Res., 29, No. 3, pp. 285-90 (1950); J.D. Res., 45, No. 5, 1499-1510(1966) and J.D. Res. 28, pp. 379-390 (1949). Briefly put, the inventorobserved and reported that transport of ions and molecules by diffusioninto narrow spaces (such as salivary retention areas) from bulksolutions (such as flowing saliva) is very slow. Significantly, theinventor noted that rapid, mass transport of a solute from bulksolutions into narrow spaces occurs if the osmolality and/or density ofthe former is greater than that of the latter. Consistent with theabove, it was further noted that (1) the habitual ingestion ofconcentrated fermentable sugars produces frequent osmolality and densitychanges in bulk oral saliva with resultant rapid and repeated conveyanceof all constituents into the microvolume salivary retention areas; and(2) ingestion of highly salted foods produces similar changes andsimilar conveyance of all constituents (even low concentrations ofcarbohydrates) into salivary retention areas.

Within a different scientific context, the inventor and his co-workersexhaustively investigated changes in enamel brought about by cariousdegradation. Model in vitro systems were constructed to simulatecariogenic environments so that the effects of proposed cariostaticagents could be ascertained and quantified. Among the earliestpublications relating to these studies was Coolidge, at al., Oral Surg.,Oral Med., & Oral Path., 8, No. 11. pp. 1204-1210 (1955) wherein it wasdisclosed that clinically produced caries-like changes in enamel couldbe substantially duplicated artificially using inorganic acid solutionscontaining both calcium and phosphate ions. Enamel changes brought aboutby, e.g., hydrochloric acid alone, do not resemble in vivo cariesformation. The cariogenicity of an acid solution of a given pH was shownto be dependent upon the product of the concentrations of calcium andphosphate (expressed as total phosphorous) and effectively independentof the absolute concentrations of each of the ions. More particularly,an essentially linear correlation was shown to exist between the ionconcentration product and cariogenicity of acid solutions havingincreasing pH's.

Recent basic research by the inventor into the effect of variousconcentrations of fluorine on mitigating the cariogenicity of acidsolutions applied in vitro provided most remarkale results. In general,these studies revealed that almost infinitismally small concentrationsof fluorine ion (e.g., on the order of 0.012 parts per million) wereneeded to substantially depress the cariogenicity of standardized"half-saturated" acidic test solutions prepared by saturating theorganic and inorganic acid solutions with the most soluble of thecalcium phosphates (calcium orthophosphate) and then doubling theirvolume with distilled water. Such "half-saturated" acid solutions hadearlier been determined imperically to be highly cariogenic. Theremarkably low fluorine concentrations necessary to render such testsolutions non-cariogenic closely approximated those which have beenreported to be extant in saliva of persons regularly ingestingfluoridated water. As such, the experimental studies appeared to providea most promising vehicle for the objective determination of the truemechanism of action of fluorine as a cariostatic agent.

In order to ascertain the precise parameters of the fluorine additionphenomenon whereby cariogenic fluids were rendered non-cariogenic,numerous experimental modifications of model cariogenic solutions weremade. Solutions of known cariogenic foodstuffs were subjected to calciumand phosphate ion augmentation (to render the solutions closely similarto those model systems which generate caries-like changes) and testedfor the effects on in vitro cariogenicity of small quantities offluorine ion. Studies were also conducted wherein saliva was providedwith fermentable refined sugars and then supplemented with varyingconcentrations of calcium, phosphate and fluorine ions before use intest systems.

The results of these tests varied quite inconsistently, with thefluorine-free "control" solutions frequently providing to be asnon-cariogenic as "test" solutions containing fluorine in concentrationswhich were earlier believed to be the minimum necessary for cariostaticactivity. Exhaustive repetitions of in vitro analyses were carried out.The results increasingly indicated that, apart from the ratherinexplicable cariostatic effects of minor quantities of fluorine oncariogenic test media, the relatively elementary process of augmentingeither the calcium or phosphate ion content of the otherwise cariogenictest fluids (especially saliva) tended to render them non-cariogenic.

The calcium or phosphate ion augmentation necessary to neutralize anotherwise cariogenic test fluid was found to be essentially independentof absolute ion concentration but (just as in the case of applicant'smuch earlier in vitro work) dependent rather upon the product of calciumand phosphate ion concentration. Also, the minimum ion product requiredwas found to vary essentially linearly in relation to pH of thesolution. Further, it was determined that such cariostaticconcentrations of the ions could be quite effectively delivered tosalivary retention areas in the mouth by combining them with osmoticallyactive substances and thereby facilitating migration of the ions fromfluids in the mouth across hydrostatic barriers.

The following examples illustrate practice of the invention in its manyaspects. As used herein the term "cariogenic substance" shall mean andinclude materials which promote the dissolution of dental enamel. Theterm, therefore includes, but is not limited to, acidic solutions andsubstances which, when contacted with saliva, tend to acidify saliva.Also included are materials providing nutrients for oral flora andconsequently enhancing the proliferation of the flora and theacidification of the floral growth medium. Comprehended by thisdefinition, therefore, are acidic foodstuffs, medications and even mouthrinses, as well as refined sugars, carbohydrates and the like which arecapable of providing soluble nutrients for floral growth. Carbohydratescomprehended as cariogenic substances treatable according to theinvention include polysaccharides (which are broken down by salivaryenzymes to di- and monosaccharides) as well as disaccharides (maltose,sucrose, lactose and the like) which are broken down in saliva tomonosaccharides such as dextrose, levulose, galactose and the like.

As used herein, the term "osmotically active substance" shall mean andinclude water soluble or miscible substances which will rapidly migrateacross hydrostatic barriers from volumes of high concentration tovolumes of low concentration. Comprehended by this definition aresoluble inorganic salts such as sodium chloride, potassium chloride,sodium sulfate and the like, soluble carbohydrates such as sucrose,glucose, fructose and the like and soluble sorbitol, mannitol, xylitol,glycerine and similar non-toxic polyhydric alcohols. Preferred isd-sorbitol which is itself known to be non-cariogenic when added tosaliva and which, unlike sodium chloride, is tasteless and will notcontribute unnecessary ions to a treatment solution.

According to one aspect of the present invention, cariogenic substancesare treated to include soluble sources of calcium or phosphate ions insubstantially uniform distribution. Substances so treated havediminished cariogenic effects because their solvation in saliva andsubsequent transport to salivary retention areas will be uniformlyaccompanied by solvation and transport of calcium or phosphate ions insuch quantities as will effectively "neutralize" the effects of pH dropsin these areas. Put another way, a material which is cariogenic byvirtue of directly or indirectly participating in the lowering of pH insalivary retention areas is rendered non-cariogenic by treatment toincorporate enough of either a calcium or phosphate ion source to keepthe acidic medium from dissolving the tooth enamel.

The efficacy of the treatment methods of the invention is most suitablydemonstrated by the results of in vitro testing for the cariogeniceffects of solutions containing equal quantities of treated andnon-treated cariogenic substances.

EXAMPLE 1

This example provides the experimental procedure employed to demonstrateutility of the present invention in prevention of carious degradation ofteeth. The methodology generally consists of exposing portions of atooth surface to contact with "test" and "control" solutions ofspecified character and then periodically observing and recordingchanges in the tooth surface. More specifically, for any givenprocedure, tooth segments subjected to test and control solutions wereobtained from the same tooth by the simple expedient of dividing asingle tooth into a desired number of segments. Tooth segments soobtained were then mounted on a small block of hard wax. Enamel surfaceswere covered with dental sticky wax (Kerr Dental Mfg. Co.) except for a2 mm×4 mm rectangular "window" which was left exposed for contact withthe solutions. Unless otherwise indicated, contact of the tooth surfacewith the solutions was carried out by immersing in a given volume of thesolution under "incubating" temperature conditions of 37° C.

EXAMPLE 2

Sucrose is treated according to the invention by dissolving in asuitable solvent, then adding to the solution so formed the desiredquantity of a water soluble source of calcium ions or phosphate ions,and finally recrystallizing the resulting solution. The preferredsolvent for use in such treatment is water. While a variety of solublesources of calcium ions such as calcium gluconate, calcium proprionate,calcium gluceptate, and calcium chloride may be employed, and whilecalcium lactate is somewhat preferred on the basis of cost, solubilityin water and palatability the benefits of sucrose treatment according tothe invention are best obtained when the source of calcium ions is asrapidly soluble in saliva as sucrose. Thus calcium gluceptate, calciumchloride and especially calcium proprionate are preferred as additivesfor sucrose. Calcium propionate is reported to dissolve in water in theamount of 55.8 grams per 100 ml water at 100° C. Similarly, whilepotassium phosphate and ammonium phosphate can provide suitable sourcesof phosphate ions, sodium phosphate (Na₂ HPO₄.12H₂ O) is preferred.

The above-noted solution and recrystallization process is much preferredto, for example, the dry mixing of sucrose with the selected ion sourcebecause it provides for greater uniformity of distribution.

Cariogenic substances in aqueous form may be treated by simple additionand mixing of the soluble ion source.

EXAMPLE 3

This example illustrates variations in the rate of solubility of calciumion sources and phosphate ion sources in water and filtered saliva.

A first series of rate of dissolution studies was carried out by placinga given quantity of selected substance evenly on the bottom surface of adry beaker. Ten milliliters of water was added to the beaker withoutstirring. The time required for the entire quantity of solute todisappear was noted. The results are set out in Table I below.

                  TABLE I                                                         ______________________________________                                                                 Time Required For                                    Substance   Quantity (grams)                                                                           Dissolution (seconds)                                ______________________________________                                        Calcium lactate                                                                           0.10         2100                                                 Calcium gluconate                                                                         0.10         1900                                                 Calcium propionate                                                                        0.10         60                                                   Calcium gluceptate                                                                        0.10          5                                                   Calcium glycero-                                                                          0.10         1200                                                 phosphate                                                                     Calcium chloride                                                                          0.10         15                                                   Na.sub.2 HPO.sub.4.12H.sub.2 O                                                            0.10         480                                                  Table sugar 1.00         1200                                                 Table sugar 0.05         40                                                   Calcium lactate                                                                            0.0013      65                                                   Calcium propionate                                                                         0.0009      10                                                   ______________________________________                                    

A second series of dissolution studies was carried out according to theprocedure noted immediately above, but using 10 ml of human salivafiltered through No. 41 Whatman filter paper. The results ae set out inTable II below.

                  TABLE II                                                        ______________________________________                                                                 Time Required For                                    Compound    Quantity (grams)                                                                           Dissolution (seconds)                                ______________________________________                                        Table sugar 0.05         85                                                   Calcium lactate                                                                           0.0013       360                                                  Calcium propionate                                                                        0.0009       15                                                   Calcium gluceptate                                                                        0.001        12                                                   ______________________________________                                    

The above results of rate of solubility serve to amplify thepreviously-noted remarks with respect to relative rates of solution ofcariogenic solids and sources of calcium ions or phosphate ions. If, forexample, a source of calcium ions employed to treat sucrose according toExample 2 is one which is less rapidly soluble in saliva than sucrose,then it is much less likely to be effective in diminishing thecariogenicity of the sugar. During a relatively brief amount of timefollowing oral intake of the treated sugar, the sucrose would rapidlydissolve and be rapidly transported into salivory retention areas by theosmotic forces noted above. If the calcium source is less rapidlysoluble then calcium ions will not effectively be transferred to theseareas along with the sugar. This aspect of the invention serves toexplain the absence of consistent results in those prior experimentalprocesses wherein some attempt was made to incorporatecalcium-containing, but phosphate-free compounds in cariogenic soliddiets. While the relative rate-of-dissolution "defects" of calcium ionsources could be modified somewhat by substantially increasing thequantities involved, the adverse effects of early dissolution andmigration of a cariogenic material to salivory retention areas are bestdealt with by use of a rapidly soluble ion source as a treating agent.In aqueous solutions according to the invention, rate of dissolution ofcalcium or phosphate ion sources does not have similar significance, itbeing necessary only to establish the proper overall concentration ofeffective ions in the solution (e.g., as indicated below, at least about3.25 mg calcium ion or about 1.08 mg phosphate ion per gram of sucrose).

EXAMPLE 4

This example illustrates the salutory effects of treatment of sucrosewith a soluble source of calcium ions. A total of fifteen experimentalprocedures (involving 35 tooth specimens) were carried out according tothe methodology of Example 1. In each instance the control solutionsemployed consisted of fresh human saliva to which was added sucrose(supplied as table sugar) in a quantity sufficient to develop a 10% byweight solution. Test solutions were identical to controls except fortheir including sucrose which was either pre-treated with a calcium ionsource (e.g., by solution and re-crystallization as in Example 2) ortreated in situ by the concurrent addition of the sucrose and calciumion source to the saliva. In two instances the test solution alsocontained a source of fluoride ions. All initial solution pH values wereapproximately 7.0 and dropped rather uniformly over the period ofobservation as a result of bacterial fermentation.

Table III below summarizes the data obtained in the course of the 14procedures. In the Table, tooth specimens are designated either ascontrol ("C") or test ("T") specimens. The various test and controlsolutions are designated according to the following abbreviations:

A. Saliva plus sucrose.

B. Saliva plus sucrose plus calcium lactate plus a source of fluorideion in a quantity sufficient to develop a fluoride ion concentration ofabout 0.10 p.p.m. or less.

C. Saliva plus sucrose plus calcium lactate.

D. Saliva plus sucrose plus calcium gluconate.

E. Saliva plus sucrose plus calcium proprionate.

F. Saliva plus sucrose plus calcium chloride.

Total quantities of calcium ion supplied to a given volume of solutionare given in terms of mg/ml, based on the molecular weight of thereagent employed. As one example, a value of "390 mg/ml" indicates that30 ml of saliva test solution contained, in addition to the quantity ofcalcium ion naturally present, 390 mg of calcium ion. Such a quantitycould be provided by addition of 3 grams of calcium lactate (supplied asa reagent in hydrated form, M.W. 308.22).

Enamel surface changes observed are designated as follows:

O=no action

⊕=white spots in isolated zones

+=caries-like alteration of total exposed surface

++=increased caries-like alteration, surface can be indented with asteel probe.

                                      TABLE III                                   __________________________________________________________________________    Procedure      Supplemental                                                                          Final                                                  No.  Specimen                                                                           Solution                                                                           [Ca]    pH Time in Solution/Surface Change                     __________________________________________________________________________    124  C    A    O       3.5                                                                              21 hrs/+;                                                                            41 hrs/+;                                                                            2 days/++;                                                                           3 days/++.                          T    B    390 mg/30 ml                                                                          3.7                                                                              21 hrs/O;                                                                            41 hrs/O;                                                                            2 days/O;                                                                            3 days/O                       126  C    A    O       3.5                                                                              12 hrs/⊕; 36 hrs/+;                                                              60 hrs/++;                                                                           4 days/++;                                                                           5 days/++.                          T.sub.1                                                                            C    390 mg/30 ml                                                                          3.7                                                                              12 hrs/O;                                                                            36 hrs/O;                                                                            60 hrs/O;                                                                            4 days/⊕;                                                                          5 days/⊕.              T.sub.2                                                                            B    390 mg/30 ml                                                                          3.7                                                                              12 hrs/O;                                                                            36 hrs/O;                                                                            60 hrs/O;                                                                            4 days/⊕                                                                           5 days/⊕.         127  C    A    O       3.4                                                                              24 hrs/⊕;                                                                        49 hrs/+;                                                                            4 days/++;                                                                           6 days/++;                                                                             9 days/++.                 T    C    390 mg/30 ml                                                                          3.6                                                                              24 hrs/O;                                                                            49 hrs/O;                                                                            4 days/O;                                                                            6 days/O;                                                                              9 days/O.             129  C    A    O       3.5                                                                              19 hrs/⊕;                                                                        28 hrs/+;                                                                            42 hrs/++.                                 T.sub.1                                                                            C    6.5 mg/ 20 ml                                                                         3.9                                                                              19 hrs/O;                                                                            28 hrs/O;                                                                            42 hrs/⊕.                              T.sub.2                                                                            C    3.25 mg/20 ml                                                                         3.8                                                                              19 hrs/O;                                                                            28 hrs/⊕;                                                                        42 hrs/+.                              132*                                                                              C.sub.1-10                                                                         A    O       3.6                                                                              24 hrs/⊕;                                                                        48 hrs/+;                                                                            54 hrs/+;                                                                            65 hrs/++.                          T.sub.1-10                                                                         C    16.25 mg/50 ml                                                                        3.9                                                                              24 hrs/O;                                                                            48 hrs/O;                                                                            54 hrs/O;                                                                            65 hrs/O to ⊕.             134  C    A    O       3.6                                                                              21 hrs/⊕;                                                                        28 hrs/+;                                                                            41 hrs/+.                                  T    C    6.5 mg/20 ml                                                                          4.0                                                                              21 hrs/O;                                                                            28 hrs/O;                                                                            41 hrs/O.                             135  C    A    O       3.7                                                                              4 hrs/⊕;                                                                         11 hrs/+;                                                                            24 hrs/+.                                  T    C    6.5 mg/ 20 ml                                                                         3.8                                                                              4 hrs/O;                                                                             11 hrs/O;                                                                            24 hrs/O.                             136  C    A    O       3.4                                                                              23 hrs/⊕;                                                                        40 hrs/+;                                                                            48 hrs/+.                                  T    D    4.46 mg/20 ml                                                                         3.4                                                                              23 hrs/O;                                                                            40 hrs/O;                                                                            48 hrs/⊕.                         138  C    A    O       3.4                                                                              5 hrs/+.                                                 T    D    4.46 mg/20 m;                                                                         3.4                                                                              5 hrs/⊕.                                        139  C    A    O       3.4                                                                              23 hrs/+;                                                                            28 hrs/+;                                                                            47 hrs/++.                                 T    D    6.5 mg/ 20 ml                                                                         3.6                                                                              23 hrs/O;                                                                            28 hrs/O;                                                                            47 hrs/⊕.                         140  C    A    O       3.3                                                                              19 hrs/+;                                                                            47 hrs/+;                                                                            64 hrs/++;                                                                           89 hrs/++.                          T    E    6.5 mg/20 ml                                                                          3.6                                                                              19 hrs/O;                                                                            47 hrs/O;                                                                            64 hrs/O;                                                                            89 hrs/O.                      142  C    A    O       3.8                                                                              3 days/⊕;                                                                        4 days/+;                                                                            4 days,                                                                              17 hrs/++.                          T    C    6.5 mg/20 ml                                                                          4.3                                                                              3 days/O;                                                                            4 days/O;                                                                            4 days,                                                                              17 hrs/O.                      149  C    A    O       3.5                                                                              6 hrs/⊕;                                                                         29 hrs/+;                                                                            47 hrs/++;                                                                           72 hrs/++.                          T    F    6.5 mg/20 ml                                                                          3.6                                                                              6 hrs/O;                                                                             29 hrs/O;                                                                            47 hrs/O;                                                                            72 hrs/O.                       150*                                                                              C.sub.1-10                                                                         A    O       3.4                                                                              26 hrs/⊕;                                                                        36 hrs/+;                                                                            47 hrs/+;                                                                            61 hrs/+to ++.                      T.sub.1-10                                                                         C    16.25 mg/50 ml                                                                        3.5                                                                              26 hrs/O;                                                                            36 hrs/O;                                                                            47 hrs/O; 61 hrs/O to                 __________________________________________________________________________                                            ⊕.                                 *10 specimens each procedure; surface changes noted in terms of average       values among the 10 specimens.                                           

The results of the fourteen procedures reported in Table III effectivelydemonstrate that carious degradation of enamel surfaces such as broughtabout by salivary bacterial fermentation of sucrose is precluded by thepresence of calcium ions. Depending on the quantity of soluble source ofcalcium ion supplied, caries-like action was inhibited for from 28 hoursto 9 days. Of the calcium ion source materials employed, calcium lactateshowed the most consistent protective effects at low doses of about0.325 mg/ml [Ca] (reported e.g., as 6.5 mg/20 ml). At lowerconcentrations, such as T₂ in procedure 129 (0.167 mg/ml) and T inprocedure 138 (0.223 mg/ml), protective effects were noted, but not foras extensive periods of time. A ratio of 3.25 mg calcium ion per gram ofsucrose can be achieved by augmentation of each gram of sucrose with,e.g. about 25.0 mg calcium lactate or 36.36 mg calcium gluconate or16.36 mg calcium propionate, and the like.

It is appropriate to note that augmentation of the test solutions withfluorine in low dosages did not appreciably enhance the protectiondonated by the calcium augmentation. Procedures 134 and 135 were carriedout with saliva from persons living in areas not supplied fluoridatedwater. Protection was obtained despite the absence of systemic or addedfluorine, a result even further obscuring the precise role of fluorinein prevention of caries. Similar good results attend augmentation ofcariogenic saliva/dextrose, saliva/maltose and saliva/cornstarchmixtures with soluble sources of calcium.

EXAMPLE 5

In order to verify that the above-noted protective effects wereexclusive to calcium ions, rather than other cations, a proceduresimilar to those of Example 4 was carried out using magnesium chloridein the place of, e.g., calcium chloride. A saliva solution containing 10percent by weight of table sugar was prepared. To a 20 ml "test" portionwas added 39.157 mg of magnesium chloride. No differences whatever werenoted in the rate of formation of caries-like lesions on the test andcontrol tooth segments. In both test and control solution, the totalexposed surface of the tooth was altered in a caries-like manner within24 hours.

EXAMPLE 6

This example illustrates the salutory effects of treatment of sucrosewith a soluble source of phosphate ions. A total of five procedures(involving 6 tooth specimens) were carried out according to themethodology of Example 1. In each instance the control solutionsconsisted of fresh human saliva to which was added sucrose (supplied astable sugar) in a quantity sufficient to develop a 10% by weightsolution. Test solutions were identical to controls except for theirincluding sucrose which was either pre-treated (e.g., by solution andre-crystallization as in Example 2) or treated in situ by the concurrentaddition of the sucrose and monohydric sodium orthophosphate (Na₂HPO₄.12H₂ O) to the saliva. All initial solution pH values wereapproximately 7.0 and dropped rather uniformly over the period ofincubation.

Table IV below summarizes the data obtained in the course of 5procedures, with "T" and "C" designating test and control tooth segmentsrespectively; "A" designating a 10% sucrose/saliva solution and "B"designating the same solution to which sodium phosphate has been added.Quantities of phosphate ion added are expressed in mg/ml. Enamel surfacechanges are designated in the same manner as in Table III.

                                      TABLE IV                                    __________________________________________________________________________    Procedure      Supplemental                                                                          Final                                                  No.  Specimen                                                                           Solution                                                                           [P.sub.T ]                                                                            pH Time in Solution/Surface Change                     __________________________________________________________________________    128  C    A    O       3.5                                                                              1 day/⊕;                                                                        11/2 days/++                                       T    B    17.29 mg/20 ml                                                                        6.0                                                                              1 day/O;                                                                            11/2 days/O                                   130  C    A    O       3.5                                                                              21 hrs/+;                                                                           46 hrs/++;                                                                           3 days/++                                   T    B     4.34 mg/20 ml                                                                        3.8                                                                              21 hrs/O;                                                                           46 hrs/O;                                                                            3 days/⊕                           131  C    A    O       3.5                                                                              22 hrs/⊕;                                                                       48 hrs/+;                                                                            2 days/++                                   T    B    2.162 mg/20 ml                                                                        3.5                                                                              22 hrs/O;                                                                           48 hrs/O;                                                                            2 days/⊕                           137  C    A    O       3.5                                                                              21 hrs/⊕;                                                                       34 hrs/+;                                                                            44 hrs/++;                                                                           50 hrs/++                            T    B    2.162 mg/20 ml                                                                        3.8                                                                              21 hrs/O;                                                                           34 hrs/O;                                                                            44 hrs/O;                                                                            50 hrs/⊕                    144  C.sub.1-2                                                                          A    O       4.4                                                                              34 hrs/+;                                                                           54 hrs/+;                                                                            70 hrs/++                                   T.sub.1-2                                                                          B    2.162 mg/20 ml                                                                        5.3                                                                              34 hrs/O;                                                                           54 hrs/O;                                                                            70 hrs/O                               __________________________________________________________________________

The results of the five procedures reported in Table IV effectivelydemonstrate that carious degradation of enamel surfaces such as broughtabout by salivary bacterial fermentation of sucrose is precluded bytreatment to provide a soluble source of phosphate ions. Protectiveeffects were achieves at low phosphate ion doses of about 0.108 mg/ml(reported as 2.162 mg/20 ml). Such augmentation of sucrose withphosphate ion can be achieved by addition, per gram of sucrose treatedof, e.g., 12.49 mg monohydric sodium orthophosphate or 4.61 mgmonohydric ammonium phosphate or 6.07 mg monohydric potassium phosphateor the like.

The data set forth in Tables III and IV establish that a cariogenicsubstance such as sucrose (provided as table sugar) can be renderedeffectively non-cariogenic by mixture with approximately 2.5 weightpercent of a soluble source of calcium ions or a soluble source ofphosphate ions, with the sources preferably having rates of dissolutionequal to or greater than that of sucrose.

While not intended to be binding upon practice of the invention, it isproposed that the avoidance of caries-like action in sucrose/saliva"test" solutions is due in part to the binding of calcium and phosphateions to salivary protein when the saliva is at or near pH 7.0. Certainof applicant's prior publications have established with substantialcertainty that calcium and phosphate ions are reversibly bound tosalivary albumins, globulins, mucin and the like. See, e.g., Lightfoot,et al., J.D. Res., 40, pp. 311-313 (1961). These proteinaceous materialshave differing isoelectric pH's in the range of 6.0 to about 3.0 and, asthe pH in the saliva test solutions drops, it is probable that these"stored" ions are gradually released into the salivary fluids to inhibitdissolution of enamel surfaces.

It is significant to note that augmentation of a cariogenic materialwith both a soluble source of calcium ions and phosphate ions is notexpected to be effective in prevention of dental caries. A firstdrawback for such procedures--which essentially mirror thoseunsuccessful procedures of the prior art--is the rapid precipitation ofinsoluble calcium phosphate salts upon the solvation of the calcium andphosphate ion sources by saliva. The calcium and phosphate ions simplywill not reach the salivary retention areas along with the dissolvedcariogenic material. It is also worthy of note that experimentalprocedures, generally patterned after those of Examples 4 and 6 andwherein there has been an attempt to supply both calcium and phosphateions, have provided rather poor protection against caries-like changesin tooth segments. This observation is not susceptible to easyexplanation, especially in view of the "closed" system employed in thein vitro test procedure. It appears, however, that once the calcium andphosphate ions are lost to the system by precipitation at close toneutral pH, they remain unavailable despite subsequent drops in pH whichwould ordinarily be expected to cause dissolution of the precipitates.

EXAMPLE 7

This example illustrates the salutory effects of treatment of variouscommercially available foodstuffs noted for their cariogenicity. In oneprocedure, segments of three human molars were mounted, waxed andimmersed in the following solutions including two popular carbonatedcola beverages (Brands "A" and "B").

Solution No. 1:

100 ml cola "A", 1 gram calcium lactate (final pH 4.5)

Solution No. 2:

100 ml cola "A", 1 gram calcium lactate, sodium fluoride to aconcentration of 0.10 ppm. (final pH 4.5)

Solution No. 3:

100 ml. cola "A", sodium fluoride to a concentration of 0.10 ppm (finalpH 3.0)

Solution No. 4:

100 ml cola "A", 1 gram calcium lactate 18 minims of 20% lactic acid(final pH 4.0)

Solution No. 5:

Same as No. 4 plus 0.05 ppm sodium fluoride (final pH 4.0)

Solution No. 6:

100 ml cola "B" (pH 3.0)

Solution No. 7:

100 ml cola "B", 1 gram calcium lactate (final pH 4.5)

Solution No. 8:

Same as No. 7 plus 18 minims 20% lactic acid (final pH 4.0)

Segments of the first molar were separately immersed in Solution Nos. 1,2 and 3; the second molar in Solutions Nos. 4 and 5; the third molar inSolution Nos. 6, 7 and 8. Tooth segments in Solution Nos. 3 and 6 werenoticeably etched after 2 hours immersion and 10 minutes immersion,respectively. Continued soaking in Solution No. 3 resulted in loss ofsurface contour of the enamel after 3 days. Similar results were broughtabout by Solution No. 6 in as little as two days. All other toothsegments had remained unchanged when the test was concluded after 4days. Substantially identical results were observed in similar testsinvolving fruit flavored soft drinks augmented by addition of dicalciumphosphate.

In another procedure, test and control saliva solutions were prepared bymixing about 45 ml of saliva with about 5.0 grams of crushed candydrops. The stirred mixture was passed through a cheese cloth filter toremove large particles. One half of the saliva/candy solution wasseparated and augmented 0.05 grams of calcium lactate and both portionswere incubated for about 26 hours at 37° C. Both solutions then had a pHof about 3.8. Split tooth specimens were then allowed to incubate in thesolutions. Within 13 hours, slight caries-like action was observed onthe control tooth and after 24 hours the total surface of the controltooth surface was affected. The test solution tooth showed no changesover the same period of time. Operating on the assumption that 5 gramsof the crushed candy drops contained about 4.5 grams of sucrose, it isonce again demonstrated that approximately 2.5 weight percent of asoluble source of calcium ions proved sufficient to inhibit thecariogenic effects of the sucrose.

The following examples illustrate the preparation and effectiveness ofmouth rinses according to the present invention.

EXAMPLE 8

The following mouth rinse solutions were prepared:

A. A 10% solution of d-sorbitol in water and further including 3%calcium lactate, food coloring and either potassium sorbate or ethanolas a preservative;

B. A 20% solution of calcium propionate in water;

C. A 10% solution of calcium proprionate in water; and,

D. A 10% solution of d-sorbitol in water and further including 2% Na₂HPO₄.12H₂ O, food coloring and either potassium sorbate or ethanol as apreservative.

The following saliva/sugar solutions were prepared:

1. A 5% solution of table sugar in saliva; and,

2. A 10% solution of table sugar in saliva.

The 5% saliva/sugar solution caused enamel changes on an incubated toothsegment within less than 24 hours and the enamel surfaces could beindented with a steel probe by the time 46 hours of incubation hadpassed.

Tooth segments incubated in equal volume mixtures of either of the 5% or10% saliva/sugar solutions and one of the mouth rinse solutions Athrough D showed no surface changes whatever for periods of from two toten days. These results establish that delivery of suitable quantitiesof either calcium or phosphate ions in the form of a mouth rinse willinhibit the adverse effects of sugar within saliva. It should be notedthat calcium proprionate appeared to substantially reduce the extent ofdecrease of pH upon incubation. In rinse solutions A and D, the calciumor phosphate ion sources are accompanied by d-sorbitol to assist in themass transfer of selected ions from the mouth to saliva trapped insalivary retention areas. In rinse solutions B and C, the proprionateserves both as a source of calcium and osmotic agent for delivery ofcalcium ions to the "target" areas.

EXAMPLE 9

In order to determine the readiness with which the rinses of Example 8would effect transfer of calcium ion reserves into salivary retentionareas, the following procedure was carried out. Four microscopic slideswere assembled in pairs separated by a 1 mm. space, providing two "open"sides 10 mm. long and 1 mm. wide for each pair. The "chamber" betweenslides was filled with a 5 percent saliva/sucrose mixture. One pair ofslides was immersed in the mouthrinse of Type A of Example 8 without theflavoring agent but with several drops of methylene blue dye. The otherslide pair was immersed in a water solution of 5 percent sucrose and theblue dye. Colored material completely filled the space in themouthrinse-soaked pair of plates within 8 seconds, while coloredmaterial from the aqueous sucrose solution did not completely penetratethe space between plates even after over 3 minutes of soaking. In stillanother procedure a solution of saliva and 5% sugar plus a few drops ofmethylene blue was used to fill the chamber between a pair of plates asdescribed above. The plates were immersed in a 3% solution of calciumlactate in water. The average time required for the blue color todisappear from the chamber was 8 minutes (three trials of 6, 8 and 10minutes). The procedure was repeated, with immersion of the chamber in a3% calcium lactate solution which additionally contained 10% d-sorbitol.The color in the chamber disappeared in approximately 9 seconds (threetrials of 8, 6 and 10 seconds), demonstrating rapid "delivery" of cariesinhibiting calcium ions to small spaces such as salivary retentionareas.

As noted above, it is a principal object of the present invention toprovide for an inhibition of carious degradation of tooth enamel inthose parts of the mouth which are most highly susceptible thereto,i.e., the salivary retention areas. To accomplish this object,cariogenic substances are augmented with either a soluble source ofcalcium ion or a soluble source of phosphate ions so that upon transportof the cariogenic material to such areas as a dissolved component insaliva, there will be an accompanying transport of "reserve" quantitiesof calcium ions or phosphate ions. The presence of such reserves insaliva retained in salivary retention areas serves to preclude toothenamel dissolution if the acidity of the retained saliva rises to asmuch as pH 2.5 or less. As a practical matter, salivary bacterialproliferation ceases at about this level of acidity.

As further noted above, applicant has discovered that, so long as theacidic salivary solution in contact with the tooth contains at least aminor quantity of either calcium ions or phosphate ions, protection canbe obtained solely by augmentation of the other ion. Put another way,protective effects are obtained at any given pH irrespective of therelative ratios of calcium ions to phosphate ions, provided that asuitable product of such concentration is obtained. "Normal" salivagenerally contains about 0.058 mg/ml calcium and about 0.168 mg/mlphosphate.

In order to illustrate this discovery, a series of test solutions ofvarying pH's was prepared using hydrochloric acid. Solutions wereaugmented with a phosphate ion source (Na₂ HPO₄.12H₂ O) and a calciumion source (calcium lactate) in varying absolute concentrations.Applicant found that dissolution of enamel was inhibited when calciumion to phosphate ion ratios (Ca/P_(T)) varied from as low as about 0.066to as high as about 4.223 so long as the required solution product ofcalcium ion times phosphate ion ([Ca]×[P_(T) ], expressed in mg/ml) wasachieved. The required solution product was found to be essentiallylinearly correlated with increases or decreases of pH ranging from about0.5 at about pH 4.5 to about 20.0 at about pH 2.9.

Table V below sets the data obtained from eight procedures involvingpreparation of acidic solutions containing varying absolute quantitiesof calcium and phosphate ions. In each instance the ordinarily harmfuleffects on tooth enamel of such acidic solutions were avoided by virtueof the required, pH related, ion product having been achieved.

                  TABLE V                                                         ______________________________________                                        Procedure      Supplied Supplied                                                                              Ca/P.sub.T                                    No.     pH     [Ca]     [P.sub.T ]                                                                            ratio [Ca] × [P.sub.T ]                 ______________________________________                                        162     4.3    1.5075   0.357   4.223 0.5382                                  163     4.5    0.1887   2.86    0.066 0.5397                                  161     3.6    3.02     0.715   4.223 2.1593                                  160     3.5    0.3775   5.72    0.066 2.1593                                  159     3.4    0.533    4.29     0.1242                                                                             2.2865                                  165     3.1    0.755    11.44   0.066 8.6372                                  166     3.0    6.644    1.573   4.223 10.451                                  164     2.9    9.06     2.145   4.223 19.4337                                 ______________________________________                                    

The FIGURE attached graphically illustrates the remarkable coincidenceof required, pH dependent "protective" ion products for solutions havinga Ca/P_(T) ratio of 4.223 (straight line) and 0.066 (dashed line).

Consistent with the above, the invention can be seen to additionallyconsist providing a mouth rinse solution including: (1) a soluble sourceof either calcium or phosphate ions; (2) a proteinaceous material towhich the "corresponding" ion is bound; and (3) an osmotically activeagent. A rinse of this type would be particularly effective in treatmentof patients having the condition known as xerostomia wherein salivaryflow is quite low and saliva cannot be counted upon to provide anyappreciable quanty of protein-bound calcium or phosphate ion. As oneexample, a rinse suitable for use by xerostomia patients may consist ofa given volume of distilled water saturated with mucin. The solutionwould then be saturated with Ca HPO₄.2H₂ O. Fluorine may be added todevelop a fluorine ion concentration of about 0.10 parts per million.Flavoring, coloring and antimicrobial materials may be added as desired.The quantities of calcium and phosphate ion provided in a rinse of thistype would provide a Ca/P_(T) ratio of from about 0.066 to about 4.223.A solution in which the product, [Ca]×[P_(T) ] exceeded about 20 wouldbe seen to provide protection in salivary retention areas wherein the pHmight drop to 3.0 or below.

Numerous modifications and variations in the invention illustrated aboveare expected to occur to those skilled in the art. Consequently onlysuch limitations as appear in the appended claims should be placedthereon.

What is claimed is:
 1. Sucrose in crystalline form having a solublesource of calcium ions uniformly distributed therethrough as a result ofdissolution of the sucrose and soluble source of calcium ions in waterand the subsequent evaporation of the water solvent, said calcium ionsource being present in a quantitative weight ratio such that upondissolution of one gram of sucrose there is also dissolved a sufficientquantity of said soluble source of calcium ions to supply to theresulting solution at least 3.25 mg of calcium ions.
 2. Sucrose incrystalline form having a soluble source of phosphate ions uniformlydistributed therethrough as a result of dissolution of the sucrose andsoluble source of phosphate ions in water and the subsequent evaporationof the water solvent, said phosphate ion source being present in aquantitative weight ratio such that upon dissolution of one gram ofsucrose there is also dissolved a sufficient quantity of said solublesource of phosphate ions to supply to the resulting solution at least1.08 mg of phosphate ions.
 3. A foodstuff containing sucrose incrystalline form having a soluble source of calcium ions uniformlydistributed therethrough as a result of dissolution of the sucrose andthe soluble source of calcium ions in water and the subsequentevaporation of the water solvent, said calcium source being present in aquantitative weight ratio such that, taking into account any differencesin the rate of dissolution of sucrose and the soluble source of calciumions under the conditons of dissolution, upon dissolution of one gram ofsucrose there is also dissolved a sufficient quantity of said solublesource of calcium ions to supply to the resulting solution at least 3.25mg of calcium ions.
 4. A foodstuff containing sucrose in crystallineform having a soluble source of phosphate ions uniformly distributedtherethrough as a result of dissolution of the sucrose and the solublesource of phosphate ions in water and the subsequent evaporation of thewater solvent, said phosphate ion source being present in a quantitativeweight ratio such that, taking into account any differences in the rateof dissolution of sucrose and the soluble source of phosphate ions underthe conditions of dissolution, upon dissolution of one gram of sucrosethere is also dissolved a sufficient quantity of said soluble source ofcalcium ions to supply to the resulting solution at least 1.08 mg ofcalcium ions.